Next generation sequencing technologies are dramatically changing biomedical research and patient diagnosis. The reducing costs of sequencing as well as robust experimental and computational protocols mean that the technology is readily available to most research and diagnostic laboratories. However, the identification of disease-causing mutations in individuals with disorders of sex development (DSD) is challenging for several reasons. These conditions are very difficult to study using classical genetic approaches since many aspects of sex development are not well-conserved in evolution and familial cases of some forms of DSD are very rare. Excluding cases where the biochemical profile indicates a specific error in steroidogenesis, it is estimated that a specific molecular diagnosis is obtained in 20% of DSD cases and that only 50% of 46,XY children with DSD will receive a definitive clinical diagnosis.
We have now performed whole exome sequencing in >130 cases of DSD, including 13 familial cases, using the Illumina HiSeq2000 platform. In this talk I will summarise our main genetic findings and highlight some of the challenges and surprises that have resulted from this approach. In around 40% of cases a known or suspected pathogenic gene mutation was found. For the remaining 60% of cases several variants of uncertain significance (VUS) were identified. The challenge is to determine the pathogenicity of at least some of these rare VUS. This may only be possible through large-scale data-sharing initiatives such as the one currently being developed within the COST action DSDnet.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology